Flupenthixol
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 1.7 Presentation, Formulation |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.3 Description |
| 3.3.2 Properties of the locally-available formulation(s) |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of locally available formulation(s) |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5. (Specific properties and composition) |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eyes, ears, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Other |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
1. NAME
1.1 Substance
Flupenthixol
Note: The International Nonproprietary Name (INN) for this
substance is flupentixol. However, the British Approved Name
(BAN) is flupenthixol and as it is generally marketed under
that name, the drug and its derivatives will be referred to
as such in this document.
(WHO, 1992; British Pharmacopoeia Commission, 1994)
1.2 Group
ATC classification index
Psycholeptics(N05)/Antipsychotics(N05A)/
Thioxanthene derivatives (N05AF)
(WHO,1992)
1.3 Synonyms
Flupenthixol
Flupentixol
Flupenthixol hydrochloride
Flupenthixol dihydrochloride
Flupentixol hydrochloride
Flupenthixol decanoate
(Z)-Flupenthixol decanoate
cis-Flupenthixol decanoate
Flupentixol decanoate
(Budavari, 1989; Reynolds, 1993)
1.4 Identification numbers
1.4.1 CAS number
Flupenthixol 2709-56-0
1.4.2 Other numbers
Other CAS numbers
Flupenthixol decanoate 30909-51-4
Flupenthixol hydrochloride 2413-38-9
RTECS
TL9900000 (Flupenthixol)
Other
LC-44 (Flupenthixol)
N-7009 (Flupenthixol)
1.5 Brand names, Trade names
Depixol Injection
Depixol-Conc Injection
Depixol Tablets
Fluanxol Tablets
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
Lundbeck Ltd., 48 Park Street, Luton LU1 3HS
Tel: (0582) 411482
(To be completed by each Centre using local data)
1.7 Presentation, Formulation
Depixol Injection
Sterile, straw-coloured solution containing cis(Z)-
flupenthixol decanoate 20 mg/mL in thin vegetable oil.
Ampoules and syringes, 1 mL (20 mg) and 2 mL (40 mg). Vials,
10 mL (200 mg)
Depixol-Conc Injection
Sterile, straw-coloured solution containing cis(Z)-
flupenthixol decanoate 100 mg/mL in thin vegetable oil.
Ampoules, 1 mL (100 mg). Vials, 5 mL (500 mg)
Depixol Tablets
Round, biconvex, yellow sugar-coated tablets with Lundbeck
logo in black on one face; diameter 9 mm. Tablets contain
racemic flupenthixol hydrochloride 3 mg. Bottles of 100
tablets
Fluanxol Tablets
0.5 mg tablet; 'Lundbeck' in black; Round, biconvex, red
sugar-coated tablets, diameter 6 mm. Tablets contain racemic
flupenthixol hydrochloride 0.5 mg. Bottles of 100 tablets 1
mg tablet; 'Lundbeck' in white; diameter 8 mm. Tablets
contain racemic flupenthixol hydrochloride 1 mg. Packs of 60
tablets, as 6 x 10 tablet blister strips.
(To be completed by each Centre using local data)
2. SUMMARY
2.1 Main risks and target organs
Acute poisoning
Main risks
Coma with respiratory depression, hypotension, convulsions
and extrapyramidal effects.
Target organs
Major target organs are the Central Nervous System (CNS) and
cardiovascular system.
Chronic poisoning
Main risks
Extrapyramidal side-effects, tardive dyskinesia and
neuroleptic malignant syndrome (NMS).
Sudden death has also occurred; cause unknown.
Target organs
Major target organ is the CNS; also kidneys as a result of
rhabdomyolysis in severe NMS.
2.2 Summary of clinical effects
Acute poisoning
Initially, drowsiness, sinus tachycardia, hypotension,
miosis.
Drowsiness may progress to coma (in agitated or aggressive
patients, hallucinations), possibly with respiratory
depression.
Tonic-clonic convulsions, muscle spasms.
Hypothermia or hyperthermia.
Extrapyramidal effects may include acute dystonic reactions
such as protruding tongue, torticollis and opisthotonos; or
Parkinsonian symptoms.
Chronic poisoning
Extrapyramidal effects
Hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
hypokinesis (e.g. Parkinsonism, akinesias).
Tardive dyskinesia
Symptoms include a range of involuntary, repetitive movements
involving the jaws, lips and tongue (orofacial dyskinesia),
and possibly more generalised movements including limb-
jerking and hyperextension of neck and trunk. Symptoms often
persist despite cessation of therapy.
Neuroleptic malignant syndrome (NMS)
Initially, withdrawal and hypoactivity progressing to
drowsiness and coma.
This is followed by severe extrapyramidal dysfunction,
including akinesia, lead-pipe rigidity progressing to
opisthotonos, tremor, oculogyric crisis and increased muscle
tone possibly resulting in dysphagia and dyspnoea.
In severe cases symptoms include fluctuating blood pressure,
tachycardia, dysuria or incontinence, peripheral
vasoconstriction, dyspnoea, sweating and hyperpyrexia. Renal
failure may occur secondary to rhabdomyolysis.
2.3 Diagnosis
Clinical diagnosis of poisoning by flupenthixol is
difficult, but must be considered in patients with impaired
consciousness and extrapyramidal features.
Flupenthixol may be measured in plasma, but levels are of
little use in the management of acute overdose.
2.4 First aid measures and management principles
Life support
Normal supportive management of the unconscious patient,
including stable side position or intubation and ventilation
if necessary.
Treat hypotension with intravenous fluids/plasma expanders.
Monitor arterial blood pressure and central venous pressure,
if unresponsive give alphamimetic agents such as dopamine(see
Section 10.7).
If patient agitated, hallucinating or convulsing, give
diazepam 0.1 mg/kg intravenously.
Gut decontamination
Give activated charcoal (50 g in adults, or 1 to 2 g/kg in
children) for any amount taken in a child and for more than
10 mg in an adult.
Do not give emetic because of potential for flupenthixol
induced coma which may result in the loss of ability to
protect airway, causing aspiration pneumonitis.
Gastric lavage should only be considered in rare cases
following recent ingestion of life-threatening amounts in
adults.
Symptomatic treatment
Neuroleptic malignant syndrome (NMS)
Institute cooling measures. In mild hyperthermia, diazepam
0.1 mg/kg intravenously may suffice. If severe (>40°C), give
dantrolene 1 to 10 mg/kg intravenously (see separate antidote
monograph).
Maintain urine output to protect renal function. Consider
alkalinizing urine in cases of rhabdomyolysis.
Extrapyramidal effects treatment
For mild extrapyramidal dysfunction, give diazepam 0.05 to
0.1 mg/kg intravenously.
If severe, give procyclidine or benztropine or orphenadrine
or diphenhydramine.
Tardive dyskinesia treatment
Withdraw flupenthixol if possible (but beware temporary
worsening of symptoms) and treat symptomatically.
Diltiazem(max. 360 mg/day) may be useful.
Elimination
Active methods of elimination are of no use in flupenthixol
poisoning. However, repeated dose activated charcoal should
be considered in serious overdose (see Section 10.4).
In NMS, haemodialysis may be required for renal failure.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Flupenthixol is wholly synthetic. Thioxanthone is
converted to an activated butadiene by a Grignard reaction
followed by dehydration. Flupenthixol is formed by 1,4
addition to the activated butadiene followed by heating or
treatment with strong alkali(Petersen et al., 1977).
3.2 Chemical structure
Structural formulae
Flupenthixol;flupenth.bmp
Note: Flupenthixol exists as two geometric isomers, the
cis(Z) and trans(E) forms. Only cis(Z)-flupenthixol is
pharmacologically active.
Molecular formulae
Flupenthixol C23H25F3N2OS
Flupenthixol decanoate C33H43F3N2O2S
Flupenthixol hydrochloride C23H25F3N2OS.2HCl
Molecular weights
Flupenthixol 434.5
Flupenthixol decanoate 588.8
Flupenthixol hydrochloride 507.4
Structural Names
Flupenthixol
2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]-
piperazin-1-yl}-ethanol
2-Trifluoromethyl-9-{3-[4-(ß-hydroxyethyl)-1-piperazinyl]-propylidene}
thioxanthene
4-{3-[2-(Trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl}-1-
piperazineethanol
Flupenthixol decanoate
2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]-
piperazin-1-yl}-ethyl decanoate
Flupenthixol hydrochloride
2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]-
piperazin-1-yl}-ethanol dihydrochloride
(Budavari, 1989; Reynolds, 1993)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Flupenthixol decanoate
Yellow
Flupenthixol hydrochloride
White or yellowish-white
3.3.1.2 State/Form
Flupenthixol decanoate
Oil
Flupenthixol hydrochloride
Powder
3.3.1.3 Description
Flupenthixol decanoate
Slight odour
Very slightly soluble in water; soluble in
ethanol; freely soluble in chloroform and
ether.
Flupenthixol hydrochloride
Soluble in water and ethanol; very slightly
soluble in chloroform; virtually insoluble in
ether.
(Budavari, 1989; Reynolds, 1993)
3.3.2 Properties of the locally-available
formulation(s)
(To be completed by each Centre using local
data)
3.4 Other characteristics
3.4.1 Shelf-life of the substance
<3.4.1 Shelf-life>No data available.
3.4.2 Shelf-life of locally available formulation(s)
Depixol Injection: Depixol-Conc Injection - Two years
Depixol Tablets - Five years
Fluanxol Tablets 0.5 mg - Five years; 1 mg - Three years
(To be completed by each Centre using local data)
3.4.3 Storage conditions
Depixol Injection; Depixol-Conc Injection -
Store at room temperature and protect from light.
Depixol Tablets; Fluanxol Tablets - Protect from light
and moisture.
(To be completed by each Centre using local data)
3.4.4 Bioavailability
(To be completed by each Centre using local data)
3.4.5. (Specific properties and composition)
<3.4.5.> Formulations of flupenthixol decanoate
intended for intramuscular injection (Depixol
Injection and Depixol-Conc Injection) are based on
Viscoleo, a light vegetable oil.
(To be completed by each Centre using local data)
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
Flupenthixol decanoate
For treatment and maintenance in schizophrenia and
related psychoses (as a depot injection), especially
in patients whose compliance with oral medication is
suspect.
Flupenthixol hydrochloride
Used orally in schizophrenia and related psychoses,
particularly with apathy and withdrawal (but not mania
or psychomotor hyperactivity); short-term adjunctive
treatment of severe anxiety; and depressive illness
(with or without anxiety).
4.2 Therapeutic dosage
4.2.1 Adults
Depixol Injection (20 mg/ml); Depixol-Conc Injection (100mg/ml)
Test dose 20 mg, then after 5 to 10 days 20 to 40 mg,
repeated at intervals of 2 to 4 weeks, adjusted
according to response. Maximum dose 400 mg weekly.
Depixol-Conc Injection is indicated when the patient
requires a high dose which could not otherwise be
given due to the large volume of the injection.
Note: Given by deep injection into the gluteal
muscle.
Depixol Tablets (3 mg)
Initially 3 to 9 mg twice daily, adjusted according to
response. Maximum dose 18 mg daily.
Fluanxol Tablets (0.5 mg; 1 mg)
Initially 1 mg (0.5 mg in elderly) in the morning,
increased after 1 week to 2 mg (1 mg in elderly) if
necessary. Maximum dose 3 mg (2 mg in elderly) daily;
divide doses above 2 mg (1 mg in elderly) into 2
portions, the second portion given before 1600 hours.
(Reynolds, 1993)
4.2.2 Children
Not recommended.
4.3 Contraindications
Flupenthixol decanoate
Depot flupenthixol decanoate is not recommended for excitable
or hyperactive patients as it may exacerbate these
features.
It is also contraindicated in Parkinsonism, severe
arteriosclerosis, senile confusional states and severe renal,
hepatic or cardiovascular disease.
Flupenthixol is best avoided in pregnancy, though there is no
evidence of teratogenicity or foetotoxicity. There is no
reason why treatment should not continue (at least after the
first trimester) in a previously unrecognised pregnancy
(Lundbeck Ltd., 1989).
Flupenthixol hydrochloride
Oral flupenthixol hydrochloride should be used with caution
in Parkinsonism, severe arteriosclerosis, senile confusional
states and severe renal, hepatic or cardiovascular
disease.
It is contraindicated in excitable or hyperactive patients in
doses below 6 mg/day as it may exacerbate these features.
Flupenthixol is best avoided in pregnancy, though there is no
evidence of teratogenicity or foetotoxicity. There is no
reason why treatment should not continue (at least after the
first trimester) in a previously unrecognised pregnancy
(Lundbeck Ltd, 1989).
Oral flupenthixol hydrochloride is not recommended for the
treatment of severe depression requiring electroconvulsive
therapy and/or hospitalisation.
5. ROUTES OF ENTRY
5.1 Oral
This is the main route of entry in acute poisonings.
5.2 Inhalation
Not applicable.
5.3 Dermal
Not applicable.
5.4 Eye
Not applicable.
5.5 Parenteral
Chronic poisoning and especially NMS has been mostly
reported after parenteral administration.
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Oral
Absorption of flupenthixol is fairly slow and incomplete,
with a bioavailability in humans of about 50% (Jorgensen
1980; Jorgensen, 1982). It is probable that flupenthixol
undergoes first-pass metabolism, either in the gut wall or
the liver, as does fluphenazine, the analogous phenothiazine
(Curry et al.,1979).
In human studies using tritiated flupenthixol hydrochloride,
Jorgensen & Gottfries (1972) found that peak serum
radioactivity occurred at 3 to 8 hours. Subjects (5) were all
post-menopausal female schizophrenics already stabilised on
flupenthixol.
This was confirmed in a later study with unlabelled
flupenthixol (Jorgensen 1980) using human volunteers (N = 3;
healthy male adults), where the time to peak (tmax) was 3 to
6 hours. In patients, average tmax was quoted as 4 hours
(Jorgensen et al., 1982).
Intramuscular
Flupenthixol decanoate is slowly released from the depot
site, with a half-life of 3 to 8 days (Jorgensen, 1980). The
decanoate ester is then rapidly hydrolysed intracellularly to
flupenthixol, with only traces of decanoate remaining in the
bloodstream (Jorgensen et al., 1971). The serum tmax for
intramuscular flupenthixol decanoate is 3 to 5 days
(Jorgensen, 1980).
6.2 Distribution by route of exposure
Flupenthixol is highly protein-bound (99%), and hence
has a large volume of distribution, Vd, of 14.1 L/kg; i.e.
987 L for a 70 kg person (Jorgensen 1980). In general, the
highest levels of flupenthixol are found in parenchymatous
organs such the lungs and liver, with much lower
concentrations in the CNS. This appears to be the case
irrespective of the route of administration.
Oral
In the rat, Jorgensen et al. (1969) found that, following
oral administration of tritiated flupenthixol, tissue
radioactivity at 8 hours post-ingestion (i.e. close to tmax)
10 mg/kg, was as follows:
Concentration Percentage
Micrograms/gram of dose
Lungs 33.1 2.3
Liver 24.8 9.3
Spleen 12.7 0.5
Kidneys 10.2 0.9
Heart 4.6 0.2
Epididymal fat 3.1 0.2
Brain 1.7 0.3
This order did not vary significantly with time.
Intramuscular
Following intramuscular 3H-flupenthixol decanoate in Viscoleo
(a light vegetable oil) to rats, Jorgensen et al. (1971)
found the following tissue radioactivity levels at 1 day
post-injection:
Concentration Percentage
Micrograms/gram of dose
Lungs 1.5 0.3
Liver 1.5 1.6
Kidneys 0.6 0.1
Spleen 0.4 -
Heart 0.12 -
Epididymal fat 0.1 0.1
Brain 0.09 -
A further 19.2% of the injected dose was still present at the
depot site.
6.3 Biological half-life by route of exposure
The kinetics of flupenthixol are complex, involving at
least a three-compartment model.
Oral
The mean biological half-life in the terminal phase (i.e.
beyond about 24 hour post-ingestion) is 19 to 39 hours,
(Jorgensen, 1980).
Intramuscular
The mean biological half-life in the terminal phase (i.e.
beyond about 14 days after injection) is 19 to 39 hours
(Jorgensen, 1980). Elimination half-life, however, was found
be from 5 to 113 days (Jorgensen et al., 1982). Depot
flupenthixol decanoate thus undergoes 'flip-flop' kinetics
(i.e. ka << ke). The significance of this is that the
terminal slope (and half-life) of the concentration/time
curve is dependent on absorption rate constant, ka, not
elimination rate constant, ke.
6.4 Metabolism
Flupenthixol has no active metabolites (Jorgensen, 1978a).
The metabolism of flupenthixol follows three main routes in
animals, regardless of the route of administration (Jorgensen
et al., 1969). These are:
Sulphoxidation
Side-chain N-dealkylation
Glucuronic acid conjugation
The major metabolites found in plasma are N-
desalkylflupenthixol and flupenthixol sulphoxide, both
inactive (Jorgensen et al., 1969, Jorgensen, 1980). However,
no compounds other than flupenthixol itself are found in the
brain, even after intramuscular injection of the decanoate
(Jorgensen, 1978a).
More N-desalkylflupenthixol is formed following oral
administration than from intramuscular, presumably because N-
dealkylation is a product of first-pass metabolism in the gut
wall and liver (Muusze et al., 1977, cited in Jorgensen,
1978b).
6.5 Elimination and excretion
Oral
In rats, 63% of a 3H-flupenthixol dose (10 mg/kg) was found
in the faeces (54% between 8 and 24 hours after ingestion);
17.4% in urine; and 2.2% remained in the body after 10 days
(Jorgensen et al., 1969).
Intramuscular
In dogs, 7 to 37% of a radiolabelled dose of flupenthixol
decanoate intramuscular appeared in urine and 21 to 54% in
faeces. Traces of drug were also found in bile (Jorgensen et
al., 1971).
In rats, only 71.4% of the dose had been excreted by 28 days,
indicating that significant amounts of drug were still
present (Jorgensen et al., 1971).
Peak urinary excretion was at about 8 days; faecal at between
3 and 6 days (Jorgensen et al., 1971). The major excretion
products were flupenthixol sulphoxide and N-
desalkylflupenthixol.
Intravenous
In rats, 59.3% of a 3H-flupenthixol dose (10 mg/kg) was found
in the faeces; 16.4% in urine; and 14.4% remained in the body
after 5 days (Jorgensen et al., 1969). The same author also
found that 12.6% of the dose was excreted in bile, suggesting
that enterohepatic circulation occurs.
Note: Systemic clearance, Cls, following intravenous infusion
was calculated by Jorgensen (1980) as 0.46 L/min (± 2.5
L/min) in healthy volunteers. This is slightly higher than
Cls for intramuscular depot administration in psychiatric
patients (Stauning et al., 1979), 0.31 L/min. This is not
surprising, since the area under the curve (AUC) is higher
for the intramuscular preparation, giving a lower calculated
clearance. Small amounts of flupenthixol are excreted in
breast milk (see 9.4.15).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
There is little data on the activity of
flupenthixol or other thioxanthenes in overdose. By
analogy with phenothiazines, however, and drawing on
descriptions of clinical findings in the literature
and internal case reports, it is likely that toxicity
is caused by the same mechanisms as those producing
its therapeutic effects: that is, by dopamine and
alpha-adrenergic receptor blockade. Flupenthixol
appears devoid of anticholinergic activity.
7.1.2 Pharmacodynamics
Neuroleptics such as flupenthixol act in
psychosis by blockage of postsynaptic dopamine
receptors in the brain (Ban & Lehmann, 1974;
Richelson, 1984). Flupenthixol is a powerful
antagonist of both D1 and D2 dopamine receptors, but
is no more potent a neuroleptic than other agents
(e.g. haloperidol) which are D2 antagonists only
(Ehmann et al., 1987). This would suggest that the
antipsychotic activity of neuroleptics is mediated by
D2 receptors, but not by D1.
Flupenthixol is an alpha-adrenergic receptor
antagonist and also depresses many hypothalamic and
hypophyseal hormones. It blocks prolactin inhibitory
factor (PIF), resulting in an increase in pituitary
prolactin secretion (Fielding & Lal, 1978).
Unlike the phenothiazines, flupenthixol resembles the
tricyclic antidepressants in some of its actions,
though not in anticholinergic activity (Kato et al.,
1969), and at low doses (1 to 2 mg/day orally) is an
effective and well-tolerated antidepressant and
anxiolytic in its own right, although contraindicated
in agitated patients (Poeldinger & Sieberns,
1983).
Like many antipsychotic drugs, flupenthixol also has
an additive effect when given with tricyclic
antidepressants (Reiter, 1969). The additive effect
may be clinically useful (Connelly & Naylor, 1987) or
potentially dangerous (Siris et al. 1978).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
An acute oral dose of approximately
29 mg (0.41 mg/kg) caused coma and
respiratory depression in a 67-year-old male
who subsequently died (NPIS London: data on
file). Cause of death was a coronary
thrombosis, with flupenthixol overdose as a
possible contributory factor.
An adult patient (age and weight not stated)
took 90 mg flupenthixol and suffered only
mild extrapyramidal signs (Mann, 1976).
0.367 mg/kg/day for 12 days caused
wakefulness, muscle weakness and headache
(NIOSH, 1989).
7.2.1.2 Children
18 to 20 mg (0.9 mg/kg) flupenthixol
in a 3´-year-old girl caused Grade III coma,
followed after 23 hours by episodes of
extrapyramidal signs, which persisted for
over 10 hours (Bailie et al.,
1981).
7.2.2 Relevant animal data
Species Route LD50
(mg/kg)
Mouse Oral 300
Mouse Subcutaneous 425
Mouse Intraperitoneal 150
Mouse Intravenous 87
Rat Oral 791
Rat Subcutaneous 258
Rat Intravenous 37
(NIOSH, 1989)
7.2.3 Relevant in vitro data
None.
7.3 Carcinogenicity
None known.
7.4 Teratogenicity
Flupenthixol crosses the placenta, with foetal serum and
amniotic fluid concentrations about one quarter the maternal
serum level (Kirk & Jorgensen, 1980). Four patients in this
study were receiving depot flupenthixol, the other one oral.
No effects were seen on foetuses.
7.5 Mutagenicity
None known.
7.6 Interactions
Tricyclic antidepressants
Flupenthixol appears to have an additive or synergistic
effect with tricyclic antidepressants (TCA), unrelated to its
antipsychotic activity. The mechanism is unclear, as only
anecdotal reports have been published, but appears to be
associated with elevated serum TCA levels (Cook et al.,
1986).
A 28-year-old paranoid schizophrenic received imipramine 150
mg/day plus depot flupenthixol 40 mg intramuscularly every
two weeks and trihexyphenydil (benzhexol) 2 mg/day.
Imipramine + desipramine levels were mildly elevated (180 to
710 nmol/L), and there was a sinus tachycardia which
disappeared on withdrawal of medication (Cook et al.,
1986).
A 31-year-old woman suffering from severe, unipolardepressive
psychosis with suicidal and homicidal hallucinations had
previously been stabilised on clomipramine 300 mg/day, L-
tryptophan 1 g twice daily and thioridazine 100 mg, but
without clinical improvement (Connelly & Naylor, 1987). 20 mg
flupenthixol decanoate were given intramuscularly, followed
by 40 mg after 3 days. There was immediate improvement in
socialisation, hallucinations and sleep pattern, but she then
had several cycles of relapses and improvements coinciding
with the fortnightly depot flupenthixol injections, despite
their being gradually increased to 80 mg. Rechallenge with
flupenthixol produced an improvement after 23 days;
rechallenge with 20 mg every two weeks produced continued
improvement until discharge 6 weeks thereafter, with the L-
tryptophan and thioridazine withdrawn. A relapse then
occurred after noncompliance with clomipramine, corrected
when it was restarted at 150 mg/day. The patient's response
was thought to be due to an interaction between clomipramine
and flupenthixol, not involving the antipsychotic effects of
the latter.
Ethanol
A double-blind study showed impairment of performance in
tests (choice reaction, co-ordination, attention) with
flupenthixol 0.5 mg three times daily for three weeks plus
ethanol 0.5 g/kg. This did not occur with flupenthixol
alone, or with single-dose haloperidol either with or without
ethanol (Linnoila, 1973; Linnoila et al., 1975). The
deterioration in performance was sufficient to severely
impair driving or handling machinery.
The mechanism of this interaction is unknown, but is presumed
to be additive CNS depression.
Eproxindine
Eproxindine is a novel Class I antiarrhythmic agent. Sudden
cardiorespiratory arrest and death occurred in a clinical
trial volunteer who was later found to have been given
flupenthixol decanoate intramuscularly 40 mg at a psychiatric
clinic, one day before receiving eproxindine 400 mg (Darragh
et al., 1985).
It is possible that this interaction was due to competition
for protein binding sites: since flupenthixol is 99% protein-
bound, a 1% reduction in binding would cause a doubling in
free fraction. This is, however, open to question as
flupenthixol has a very large volume of distribution (14.1
L/kg) and plasma drug levels would therefore not rise greatly
(Simister & Jorgensen, 1985).
Arecoline
Chewing by two patients of betel nut, Areca catechu (Palmae),
was accompanied by exacerbation of extra-pyramidal side-
effects (see Section 7.7) from both depot flupenthixol and
depot fluphenazine (Deahl, 1987). This was thought due to
the cholinergic activity of arecoline, a tertiary amine
found in the nut, which would antagonise the effect of
procyclidine, given to both patients to control
extrapyramidal signs.
Monoamine oxidase inhibitors (MAOI)
No published evidence could be found for an interaction
between flupenthixol and MAOI. However, MAOI could
theoretically affect flupenthixol pharmacodynamics, so it may
be advisable to allow 7 days between cessation of MAOI
therapy and commencement of flupenthixol (Lundbeck Ltd.,
1989).
7.7 Main adverse effects
Sudden death
Sudden death occurred in three patients aged 23-29 receiving
depot flupenthixol decanoate, which was the sole medication
in two. None was receiving the drug for the first time. The
last doses given were 30 mg, 20 mg and 40 mg, with death
occurring 1 day, 1 week and 1 week respectively after the
final dose (Turbott & Smeeton, 1984).
The causes of death were unknown in all cases, and postmortem
findings were unremarkable. A possible clue may be that the
deaths occurred at about the same time post-dose as the
highest incidence of extrapyramidal symptoms, and close to
tmax for intramuscular flupenthixol decanoate. Similar cases
have been reported with phenothiazines (Whyman, 1976;
Solomon, 1977).
Extrapyramidal signs & symptoms
The dopamine antagonist activity of flupenthixol (and other
neuroleptics) is also responsible for its extrapyramidal side
effects, which occur in approximately 25% of patients
(British National Formulary, 1989). They are caused by
disturbance of the dopamine-acetylcholine balance in the
basal ganglia (Carlsson, 1978).
This may cause an acetylcholinergic excess, resulting in
hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
dopaminergic excess leading to hypokinesias (e.g.
Parkinsonism, akinesias) (Bell et al., 1980).
Extrapyramidal symptoms appear rapidly after oral
administration, and within 1 to 3 days of depot injection.
They may persist for about five days (Lundbeck Ltd.,
1989).
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome (NMS) is a rare but serious
side- effect of many neuroleptic drugs (Szabadi, 1984). It
may be caused by flupenthixol (Bates & Courtenay-Evans, 1984;
Tomson, 1986).
There are three groups of symptoms:
Catatonic (usually the earliest to appear)
Withdrawal and hypoactivity progressing to drowsiness and
coma (Weinberger & Kelly, 1977).
Extrapyramidal
Akinesia; lead-pipe rigidity (NPIS London: case report
77/118) progressing to opisthotonos; tremor; oculogyric
crisis; increased muscle tone possibly resulting in dysphagia
and dyspnoea (Weinberger & Kelly, 1977).
Autonomic
Fluctuating blood pressure; tachycardia; peripheral
vasoconstriction; dyspnoea; sweating; dysuria or
incontinence; hyperpyrexia (Weinberger & Kelly, 1977).
This combination of extrapyramidal signs with hyperpyrexia
should be diagnostic.
NMS carries a 20% mortality rate (Caroff, 1980), hyperpyrexia
(or complications secondary to it, e.g. respiratory failure)
being the major cause of death. NMS-induced hyperpyrexia may
be more prevalent in hot climates (Singh, 1983).
NMS is thought to be caused by excessive dopamine receptor
blockade (Burke et al., 1981; Henderson, 1981). However,
some other precipitating factor (e.g. concurrent lithium
therapy, which would prevent compensating up-regulation of
dopamine receptors in neuroleptic therapy) is probably
required (Szabadi, 1984).
Tardive dyskinesia
Tardive dyskinesia is a serious extrapyramidal side effect of
neuroleptic drug therapy. It usually occurs in patients on
long- term depot medication, and has been seen with both
flupenthixol and fluphenazine (Barnes & Wiles, 1983).
Symptoms include a range of involuntary, repetitive movements
involving the jaws, lips and tongue (orofacial dyskinesia),
and possibly more generalised movements including limb-
jerking and hyperextension of neck and trunk (Dick &
Saunders, 1981). Symptoms often persist despite cessation of
therapy.
The syndrome is thought to be caused by chronic dopaminergic
blockade, leading to up-regulation of receptors and
hypersensitivity (Klawans, 1973), a theory supported by the
fact that severity of symptoms is inversely related to plasma
flupenthixol levels (Barnes & Wiles, 1983). The same authors
also found that severity correlated with patient age.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Drowsiness, sinus tachycardia, hypotension,
miosis. Progressive coma (in agitated or aggressive
patients, hallucinations); possibly respiratory
depression. Tonic-clonic convulsions, muscle spasms.
Hypothermia or hyperthermia.
Extrapyramidal effects are hyperkinesis (i.e. acute
dystonic reactions such as protruding tongue,
torticollis and opisthotonos) or hypokinesis (e.g.
Parkinsonism, akinesia).
9.1.2 Inhalation
Not known.
9.1.3 Skin exposure
Not known.
9.1.4 Eye contact
Not known.
9.1.5 Parenteral exposure
Not known from acute overdose, but would be as
for ingestion. Onset of symptoms could be delayed for
several days (tmax for intramuscular depot
flupenthixol is 3 to 5 days):
Drowsiness, sinus tachycardia, hypotension, miosis.
Progressive coma (in agitated or aggressive patients,
hallucinations); possibly respiratory depression.
Tonic-clonic convulsions, muscle spasms. Hypothermia
or hyperthermia.
Extrapyramidal effects
Hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
Hypokinesis (e.g. Parkinsonism, akinesia)
Accidental intravenous injection of intramuscular
flupenthixol preparations has not been reported, but
due to the oily nature of the preparation, there could
be a risk of embolus formation.
9.1.6 Other
Not known.
9.2 Chronic poisoning
9.2.1 Ingestion
Extrapyramidal effects
Hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
Hypokinesis (e.g. Parkinsonism, akinesias).
Tardive dyskinesia
Normally only seen in patients on long-term therapy,
and therefore unlikely to affect patients receiving
oral flupenthixol only. However, in the event of this
occurring, symptoms would include a range of
involuntary, repetitive movements involving the jaws,
lips and tongue (orofacial dyskinesia), and possibly
more generalised movements including limb-jerking and
hyperextension of neck and trunk. Symptoms often
persist despite cessation of therapy.
Neuroleptic malignant syndrome (NMS)
Normally only seen in patients on long-term, high-dose
therapy, and therefore unlikely to affect patients
receiving oral flupenthixol only. However, in the
event of its occurring, symptoms would include:
Catatonic (usually the earliest to appear):
Withdrawal and hypoactivity progressing to drowsiness
and coma.
Extrapyramidal: Akinesia; lead-pipe rigidity
progressing to opisthotonos; tremor; oculogyric
crisis; increased muscle tone possibly resulting in
dysphagia and dyspnoea.
Autonomic: Fluctuating blood pressure; tachycardia;
peripheral vasoconstriction; dyspnoea; sweating;
dysuria or incontinence; hyperpyrexia.
NMS carries a 20% mortality rate. Hyperpyrexia (or
complications secondary to it, e.g. cerebrovascular
injury) is the major cause of death. This combination
of extrapyramidal signs with hyperpyrexia should be
diagnostic.
9.2.2 Inhalation
Not known
9.2.3 Skin exposure
Not known
9.2.4 Eye contact
Not known
9.2.5 Parenteral exposure
Extrapyramidal effects
Hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
Hypokinesis (e.g. Parkinsonism, akinesias).
Tardive dyskinesia
Symptoms include a range of involuntary, repetitive
movements involving the jaws, lips and tongue
(orofacial dyskinesia), and possibly more generalised
movements including limb-jerking and hyperextension of
neck and trunk. Symptoms often persist despite
cessation of therapy.
Neuroleptic malignant syndrome (NMS)
Normally only seen in patients on long-term, high-dose
therapy, but it is rare.Symptoms include:
Catatonic (usually the earliest to appear):
Withdrawal and hypoactivity progressing to drowsiness
and coma.
Extrapyramidal: Akinesia; lead-pipe rigidity
progressing to opisthotonos; tremor; oculogyric
crisis; increased muscle tone possibly resulting in
dysphagia and dyspnoea.
Autonomic: Fluctuating blood pressure; tachycardia;
peripheral vasoconstriction; dyspnoea; sweating;
dysuria or incontinence; hyperpyrexia.
NMS carries a 20% mortality rate. Hyperpyrexia (or
complications secondary to it, e.g. cerebrovascular
injury) is the major cause of death. This combination
of extrapyramidal signs with hyperpyrexia should be
diagnostic.
9.2.6 Other
Not known.
9.3 Course, prognosis, cause of death
Mild poisoning
Drowsiness, sinus tachycardia, hypotension, miosis.
Moderate poisoning
Drowsiness progresses to coma (in agitated or aggressive
patients, hallucinations). Hypothermia, muscle spasms.
Extrapyramidal effects
Hyperkinesis (i.e. acute dystonic reactions such as
protruding tongue, torticollis and opisthotonos); or
hypokinesis (e.g. Parkinsonism, akinesias). Symptoms may
persist for up to 48 hours after oral overdose.
Severe poisoning
Deep coma, possibly respiratory depression. Tonic-clonic
convulsions.
No fatalities have been reported from overdose of
flupenthixol alone. However, in acute overdose the most
likely cause of death would be anoxic brain damage or other
lesions caused by respiratory depression, or cardiac arrest
due to "torsades de pointes" arrhythmias..
Neuroleptic malignant syndrome (NMS), which is seen in
patients on long-term, high-dose treatment, carries a 20%
mortality rate. Hyperpyrexia (or complications secondary to
it, e.g. cerebral injury) is the major cause of death.
Hyperpyrexia should therefore be regarded seriously,
especially in chronic or acute-on-chronic poisoning, as it
may presage the onset of NMS. The combination of extra-
pyramidal signs with hyperpyrexia should be diagnostic.
Symptoms include:
Catatonic (usually the earliest to appear): Withdrawal and
hypoactivity progressing to drowsiness and coma.
Extrapyramidal: Akinesia; lead-pipe rigidity progressing to
opisthotonos; tremor; oculogyric crisis; increased muscle
tone possibly resulting in dysphagia and dyspnoea.
Autonomic: Fluctuating blood pressure; tachycardia;
peripheral vasoconstriction; dyspnoea; sweating; dysuria or
incontinence; hyperpyrexia.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute
Shock and hypotension are likely in significant
overdose (NPIS London, data on file). Cardiotoxic
effects such as conduction defects and ventricular
dysrhythmias have not been reported with flupenthixol
or other thioxanthenes. However, these do occur after
over-dosage with other neuroleptics such
asthioridazine, chlorpromazine and haloperidol
(Niemann et al., 1981; Lumpkin et al., 1979).
Further, flupenthixol does not cause the
anticholinergic effects associated with tricyclic
antidepressants (Mann, 1976).
"Torsades de pointes" type arrhythmia may be observed
in severe poisoning with coma. (Jacobsen D, personal
communication).
Chronic
None known.
Acute-on-chronic
Hypertension or hypotension may occur as a feature of
the neuroleptic malignant syndrome (NMS). One patient
in NMS had blood pressure varying between 100/60 and
170/120 (Tomson, 1986); another had intermittent
hypotension associated with sweating and tachypnoea
(Bates & Courtenay-Evans, 1984).
9.4.2 Respiratory
Acute
Respiratory depression occurred in a patient who took
an overdose of 29 mg flupenthixol (NPIS London, data
on file).
Chronic
None known.
Acute-on-chronic
Hypoxia due to decreased chest wall compliance in NMS
(Tomson, 1986)
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Acute
Drowsiness progressing to coma (NPIS London,
data on file; Bailie et al., 1981).
Hallucinations have occurred in agitated or
aggressive patients with phenothiazine
overdose (Barry et al., 1973), so might
conceivably occur with flupenthixol.
Tonic-clonic convulsions have occurred in a 5
year old child (NPIS London, case
76/18193).
Extrapyramidal effects: Hyperkinesis (i.e.
acute dystonic reactions such as protruding
tongue, torticollis and opisthotonos) (Bailie
et al., 1981); or hypokinesis (e.g.
Parkinsonism, akinesias) (NPIS London, case
77/118).
Chronic
Tardive dyskinesia: Symptoms include a range
of involuntary, repetitive movements
involving the jaws, lips and tongue
(orofacial dyskinesia), and possibly more
generalised movements including limb-jerking
and hyperextension of neck and trunk (Dick &
Saunders, 1981). Symptoms often persist
despite cessation of therapy, and severity
appears to be inversely proportional to serum
flupenthixol levels (Barnes & Wiles,
1983).
Long-term, high-dose flupenthixol may lead to
paradoxical excitability, restlessness and
aggression (Barnes & Bridges, 1980).
Wakefulness and headache was caused by
0.367 mg/kg/day for 12 days (NIOSH,
1989).
Acute-on-chronic
NMS: Withdrawal and hypoactivity progressing
to drowsiness and coma (Weinberger & Kelly,
1977). Extrapyramidal symptoms include
akinesia; lead-pipe rigidity (NPIS London:
case report 77/118) progressing to
opisthotonos; tremor; oculogyric crisis
(Weinberger & Kelly, 1977).
9.4.3.2 Peripheral nervous system
Acute
None known. Chlorpromazine and other
phenothiazines have local anaesthetic
properties, probably associated with membrane
stabilising activity (Seeman, 1972), but this
has not been reported with flupenthixol.
Chronic
None known.
Acute-on-chronic
None known.
9.4.3.3 Autonomic nervous system
Acute
Shock and hypotension may occur (NPIS London,
data on file).
Acute
Shock
Chronic
None known.
Acute-on-chronic
NMS: Fluctuating blood pressure; tachycardia;
peripheral vasoconstriction; sweating;
hyperpyrexia (Weinberger & Kelly, 1977).
Acute
Shock
9.4.3.4 Skeletal and smooth muscle
Acute
Extrapyramidal effects may cause hyperkinesis
(i.e. acute dystonic reactions such as
protruding tongue, torticollis and
opisthotonos), or hypokinesis (e.g.
Parkinsonism, akinesias) (Bell et al.,
1980).
Chronic
Tardive dyskinesia: Symptoms include a range
of involuntary, repetitive movements
involving the jaws, lips and tongue
(orofacial dyskinesia), and possibly more
generalised movements including limb-jerking
and hyperextension of neck and trunk (Dick &
Saunders, 1981). Symptoms often persist
despite cessation of therapy.
0.367 mg/kg/day for 12 days caused muscle
weakness (NIOSH, 1989).
Acute-on-chronic
In NMS, increased muscle tone may occur,
possibly resulting in dysphagia and dyspnoea
(Weinberger & Kelly, 1977). Elevated CPK
levels have been reported in several cases
(McAllister, 1978; Henderson & Wooten, 1981),
possibly reflecting rhabdomyolysis after
muscle hypertonia.
Laryngo-pharyngeal dystonia has been
suggested as a possible mechanism in sudden
death from depot flupenthixol (Turbott &
Smeeton, 1984).
9.4.4 Gastrointestinal
Acute
None known. Nausea and vomiting do not appear to be a
feature of overdose.
Chronic
None known.
Acute-on-chronic
None known. Acute intestinal dilation has been
reported in a fatal case(Turbott & Smeeton,
1984).
9.4.5 Hepatic
Acute
One patient became jaundiced after recovery from a
multiple overdose of flupenthixol, amylobarbitone and
ethanol (NPIS London, case 77/118). It is not known
whether flupenthixol played any part in this.
Chronic
None known. Flupenthixol does not appear to possess
the potential for hepatotoxicity of some
phenothiazines, such as chlorpromazine.
Acute-on-chronic
Elevated AST, LDH and alkaline phosphatase levels have
been reported in neuroleptic malignant syndrome (Smego
& Durack, 1982). The mechanism is unknown, but may be
secondary to hyperthermia.
9.4.6 Urinary
9.4.6.1 Renal
Acute
None known.
Chronic
None known.
Acute-on-chronic
Acute renal failure has been reported in
neuroleptic malignant syndrome (NMS) from
flupenthixol (Tomson, 1986), thought to be
due to rhabdomyolysis after muscle
hypertonia. Elevated CPK levels have been
reported in several other cases of NMS
(McAllister, 1978; Henderson & Wooten,
1981).
9.4.6.2 Other
Acute
None known.
Chronic
Urinary incontinence has occurred with long-
term depot treatment with flupenthixol (and
fluphenazine). Enuresis occurred within
seven days of each injection, stopped after
withdrawal of treatment, and recurred on re-
challenge. All patients were women under 35
years (Shaikh, 1978).
Acute-on-chronic
None known.
9.4.7 Endocrine and reproductive systems
Acute
None known.
Chronic
Flupenthixol depresses many hypothalamic and
hypophyseal hormones. It blocks prolactin inhibitory
factor (PIF), resulting in an increase in pituitary
prolactin secretion (Fielding & Lal, 1978).
Priapism has been reported with other neuroleptics
(thioridazine, fluphenazine, chlorpromazine,
trifluoperazine; haloperidol), but not with
flupenthixol (Fishbain, 1985).
Acute-on-chronic
None known.
9.4.8 Dermatological
Acute
None known.
Chronic
Not known from flupenthixol. Some phenothiazines have
caused photosensitisation.
Acute-on-chronic
Sweating may occur in NMS (Bates & Courtenay-Evans,
1984).
9.4.9 Eyes, ears, nose, throat: local effects
Acute
Hypersalivation was reported in a 3-year-old who had
taken 18 to 20 mg flupenthixol 33 hours previously
(Bailie et al., 1981)
Acute
Hypersalivation
Chronic
None known from flupenthixol. However, long-term
treatment with thiothixene (another thioxanthene) may
cause fine lenticular pigmentation (Haase et al.,
1967; Mason, 1977). Only very mild visual problems
were noted, shortly after the start of treatment.
Acute-on-chronic
Dry cough has been reported in NMS (Bates & Courtenay-
Evans, 1984).
Acute
Hypersalivation
9.4.10 Haematological
Acute
None known.
Chronic
None known from flupenthixol. Blood dyscrasias
progressing to agranulocytosis have occurred with some
phenothiazines (DuComb & Baldessarini, 1977).
Acute-on-chronic
Leucocytosis of 12-30 x 109 cells/L may occur in NMS
(Smego & Durack, 1982; Bates & Courtenay-Evans, 1984;
Tomson, 1986).
9.4.11 Immunological
Acute
None known.
Chronic
None known.
Acute-on-chronic
None known
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Acute
Acidosis is possible if respiratory
depression occurs.
Chronic
None known.
Acute-on-chronic
In neuroleptic malignant syndrome,
respiratory or metabolic acidosis is possible
because of respiratory depression or
rhabdomyolysis.
9.4.12.2 Fluid and electrolyte disturbances
Acute
None known.
Chronic
None known.
Acute-on-chronic
Hyperkalaemia may occur secondary to NMS.
A patient with NMS had marked hyponatraemia.
However, this was possibly not related to
flupenthixol as he also had psychogenic
polydipsia (Tomson, 1986)
9.4.12.3 Other
Acute
None known.
Chronic
None known.
Acute-on-chronic
Patients with NMS may develop marked
hyperpyrexia (Bates & Courtenay-Evans, 1984;
Tomson, 1986).
9.4.13 Allergic reactions
Acute
None known.
Chronic
None known.
Acute-on-chronic
None known.
9.4.14 Other clinical effects
None known.
9.4.15 Special risks
Pregnancy
Flupenthixol crosses the placenta, with foetal serum
and amniotic fluid concentrations about one quarter
the maternal serum level (Kirk & Jorgensen, 1980).
Four patients in this study were receiving depot
flupenthixol, the other one oral. No effects were seen
on the foetuses, confirming the findings of animal
studies (Lundbeck Ltd., 1989).
Breast feeding
Kirk & Jorgensen (1980) found that flupenthixol was
excreted in breast milk at a concentration about 30%
higher than the maternal serum level. However,
Mathesen & Skjæraasen (1988) found that milk levels
closely paralleled maternal serum levels, except when
milk triglyceride levels were elevated. Given the
lipophilicity of flupenthixol, this is not
surprising.
Flupenthixol was detectable in the child on only one
occasion in the two studies, and was not thought by
either authority to be a hazard.
Enzyme deficiency
None known.
9.5 Other
Sudden death occurred in three patients aged 23-29
receiving depot flupenthixol, which was the sole medication
in two. None was receiving the drug for the first time. The
last doses given were 30 mg, 20 mg and 40 mg, with death
occurring 1 day, 1 week and 1 week respectively after the
final dose (Turbott & Smeeton, 1984).
The causes of death were unknown in all cases, and postmortem
findings were unremarkable. A possible clue may be that the
deaths occurred at about the same time post-dose as the
highest incidence of extrapyramidal symptoms, and close to
tmax for intramuscular flupenthixol decanoate. Similar cases
have been reported with phenothiazines (Whyman, 1976;
Solomon, 1977).
9.6 Summary
Not applicable
10. MANAGEMENT
10.1 General principles
Flupenthixol appears to be relatively safe in overdose.
A series of 28 overdoses followed up by NPIS London (Crome et
al, 1978) failed to show any serious toxicity.
Since flupenthixol is fairly slowly absorbed from the gut,
with tmax = 3 to 6 hours (Jorgensen, 1980; Jorgensen et al.,
1982), initial management of acute overdose should be aimed
primarily at prevention of absorption.
The major symptoms seen in acute overdose are likely to be
CNS depression, with the possibility of respiratory
depression (NPIS London, data on file), especially if alcohol
has also been taken. Extrapyramidal effects are also probable
(Mann, 1976; Bailie et al., 1981).
There is a danger of shock and hypotension in significant
overdose. However, flupenthixol does not cause the
cardiotoxic effects seen after overdosage with other
neuroleptics such as thioridazine, chlorpromazine and
haloperidol (Niemann et al., 1981; Lumpkin et al., 1979); nor
does it cause the anticholinergic effects associated with
tricyclic antidepressants (Mann, 1976).
Further treatment should therefore be basically supportive,
with particular attention to maintaining adequate ventilation
and blood pressure. Antiparkinsonian drugs should be given as
required.
Methods of active removal, such as haemodialysis or
haemoperfusion, are unlikely to be of use, since flupenthixol
is highly protein-bound and has a large volume of
distribution (Jorgensen, 1980).
10.2 Relevant laboratory analyses
10.2.1 Sample collection
For flupenthixol analysis, blood should be
collected into EDTA tubes, and the plasma separated
and frozen pending analysis. For monitoring of
therapy, samples for quantitative analysis should be
taken not less than 10 hours post-dose (Balant- Gorgia
et al., 1985b).
10.2.2 Biomedical analysis
None specifically relevant in acute overdose.
Arterial blood gases (pO2, pH) should be monitored in
unconscious patients.
If neuroleptic malignant syndrome suspected, monitor
temperature, arterial blood gases (pO2, pH), serum
electrolytes, glucose and CPK.
10.2.3 Toxicological analysis
Analysis of flupenthixol in body fluids is
difficult, as (in common with other neuroleptics) the
drug is administered in small doses and has a very
large volume of distribution, giving low serum
concentrations even in overdose.
Detection
Colour tests:
Refer to Section 8.1.1.
Thin-layer chromatography:
Refer to Section 8.1.2.
Quantitative analysis
Refer to Section 8.1.3. Plasma levels are unlikely to
affect the management of acute overdose.
It should be borne in mind that oral preparations of
flupenthixol contain a racemic mixture of the cis(Z)
and trans(E) isomers. Since GLC cannot distinguish
between them, results obtained by this method should
be halved to give the concentration of active drug.
This does not apply to depot preparations.
10.2.4 Other investigations
Not relevant.
10.3 Life supportive procedures and symptomatic/specific treatment
Life support
CNS and respiratory depression
Normal supportive management of the unconscious patient.
Measure arterial blood gases (pO2, pH) and/or respiratory
rate; intubate and ventilate if necessary.
Hypotension
Although flupenthixol itself does not cause acute
cardiotoxicity, patients who overdose on it frequently also
have access to cardiotoxic drugs such as tricyclic
antidepressants. If this is suspected, monitor ECG.
For hypotension, give intravenous fluids or plasma expanders
initially. This may be all that is required to restore
adequate blood pressure.
If hypotension is unresponsive to intravenous fluids, give
alphamimetic agents such as dopamine.
Other
For agitation, hallucinations or convulsions give diazepam
0.1 mg/kg.
Symptomatic treatment
Neuroleptic Malignant Syndrome
If NMS suspected, monitor temperature, arterial blood gases
(pO2, pH), serum electrolytes, glucose and CPK.
Cooling measures should be instituted, e.g. diazepam 0.1
mg/kg may be sufficient in mild hyperthermia (Smego & Durack,
1982). If severe (>40°C), dantrolene 1 to 10 mg/kg may be
effective, as it relieves muscle rigidity in malignant
hyperthermia (Cameron & Borthwick, 1983). Treat
extrapyramidal effects conventionally. Give procyclidine 5
to 10 mg intravenously, repeated as necessary (maximum dose
in 24 hours 20 mg), or benztropine 2 mg intravenously or
intramuscularly stat. Orphenadrine 20 mg intramuscularly
stat was also effective in a child (Bailie et al., 1981).
Because of the risk of secondary renal damage due to
rhabdomyolysis, adequate fluid balance should be maintained.
Consider alkalizing urine. Haemodialysis may be required in
renal failure (Tomson, 1986).
Extrapyramidal effects
If extrapyramidal signs are mild (e.g. neck stiffness only),
and are not causing the patient distress, diazepam 0.05 to
0.1 mg/kg may suffice.
For more severe symptoms, give procyclidine 5 to 10 mg
intravenously, repeated as necessary (maximum dose in 24
hours 20 mg), or benztropine 2 mg (adults) intravenously or
intramuscularly stat. Orphenadrine 20 mg intramuscularly stat
was also effective in a child (Bailie et al., 1981).
Diphenhydramine 2 mg/kg (maximum 50 mg) intravenously stat
relieves symptoms rapidly, but may cause further sedation and
should be given with caution in drowsy patients.
Smaller doses of all these agents may be required in mixed
overdose with tricyclic antidepressants, due to the
possibility of anticholinergic symptoms.
After initial control of the acute dystonic reaction, oral
antiparkinsonian therapy should continue for 48 to 72 hours
to prevent recurrence of symptoms due to the long half-life
of flupenthixol. This may be given on an outpatient basis
(Corre et al., 1984). Suitable oral dosages are benztropine
1 to 2 mg twice daily, or diphenhydramine 50 mg three times
daily.
Tardive dyskinesia
Tardive dyskinesia has only been seen in long-term
neuroleptic therapy. It is therefore unlikely to be seen in
acute overdose, or with oral therapy.
No truly effective treatment for tardive dyskinesia has yet
been established (Dick & Saunders, 1981). Current
recommendations consist of cessation of the drug and
symptomatic management of side- effects. Withdrawal of
flupenthixol is likely to lead initially to worsening of the
symptoms, though these tends to improve after some months.
Diltiazem in doses up to 360 mg/day may be effective in
relieving tardive dyskinesia, but requires further
investigation (Ross et al., 1987).
10.4 Decontamination
Activated charcoal
The efficacy of activated charcoal in flupenthixol overdose
has not been established, but it is probably useful since it
is effective with phenothiazines.
Give activated charcoal (50 g in adults, 1 to 2 mg/kg in
children) for any amount taken in a child and for more than
10 mg in an adult.
Due to possible enterohepatic recycling, repeated-dose
activated charcoal may be useful in large overdoses
(Jorgensen et al., 1969).
Emesis and gastric lavage
Gastric lavage should only be considered in rare cases
following recent ingestion of life-threatening amounts in
adults.
Do not give emetic because of potential for flupenthixol-
induced coma which may result in the loss of ability to
protect airway, causing aspiration pneumonitis.
10.5 Elimination
Active methods of elimination (forced diuresis,
haemoperfusion, haemodialysis, alteration of urinary pH) are
ineffective due to flupenthixol's large volume of
distribution, and a high degree of protein binding
(Jorgensen, 1980).
In patients with neuroleptic malignant syndrome,
haemodialysis or peritoneal dialysis may be required for
renal failure (Tomson, 1986).
10.6 Antidote treatment
10.6.1 Adults
Not applicable.
10.6.2 Children
Not applicable.
10.7 Management discussion
No discussion.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
(Note: There are very few cases of flupenthixol
overdose reported in the literature, and those tend to be
anecdotal. Other reports of overdose are available from NPIS
London's case files).
Case 1
Flupenthixol 18 to 20 mg (0.9 mg/kg) in a 3´- year-old girl
caused drowsiness after 90 minutes, progressing to Grade III
coma after 3 hours. Gastric lavage was performed, without
result (following attempted emesis with salt water).
Consciousness improved over the next 20 hours without further
treatment.
At 23 hours post-ingestion she started suffering a series of
episodes of extrapyramidal effects, which persisted for over
10 hours. These initially included neck extension and
catalepsy; then festinating gait and facial and body
rigidity; and finally (at 33 hours) dysphagia and salivation,
treated with orphenadrine 20 mg. Recovery was complete by 48
hours (Bailie et al., 1981).
Case 2
An adult patient (age and weight not stated) took 90 mg
flupenthixol and suffered only mild extrapyramidal signs
(Mann, 1976).
11.2 Internally extracted data on cases
To be completed by each Centre using local data.
11.3 Internal cases
To be completed by each Centre using local data
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
Not applicable.
12.2 Specific preventive measures
No data available.
12.3 Other
Not applicable.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES),
COMPLETE ADDRESS(ES)
Author Mr N. Thompson MSc (Med Sci) DipInfSci BA
National Poisons Unit
Avonley Road
London SE14 5ER
United Kingdom
Date March 1990
Peer Review Strasbourg, France, April 1990
Update Peer Review Berlin, Germany, October 1995
(Group members: Dr A. Jaeger, Dr C. Pulce,
Dr G Volans)